EP0669938A1 - Peptidderivate von alpha-msh und deren anwendung - Google Patents

Peptidderivate von alpha-msh und deren anwendung

Info

Publication number
EP0669938A1
EP0669938A1 EP94928428A EP94928428A EP0669938A1 EP 0669938 A1 EP0669938 A1 EP 0669938A1 EP 94928428 A EP94928428 A EP 94928428A EP 94928428 A EP94928428 A EP 94928428A EP 0669938 A1 EP0669938 A1 EP 0669938A1
Authority
EP
European Patent Office
Prior art keywords
trp
arg
gly
phe
homophe
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP94928428A
Other languages
English (en)
French (fr)
Other versions
EP0669938B1 (de
Inventor
Lucien Dussourd D'hinterland
Anne-Marie Rés. Herbemont Le Galoubet PINEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institut Europeen de Biologie Cellulaire
Original Assignee
Institut Europeen de Biologie Cellulaire
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institut Europeen de Biologie Cellulaire filed Critical Institut Europeen de Biologie Cellulaire
Publication of EP0669938A1 publication Critical patent/EP0669938A1/de
Application granted granted Critical
Publication of EP0669938B1 publication Critical patent/EP0669938B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C07K14/68—Melanocyte-stimulating hormone [MSH]
    • C07K14/685—Alpha-melanotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/04—Preparations for care of the skin for chemically tanning the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention notably has peptide derivatives of ⁇ -MSH ("Melanocyte Stimulating Hormone”), presented in Lipoyl-Peptides form.
  • ⁇ -MSH Melt Stimulating Hormone
  • the main reason is the extreme ubiquity of ⁇ -MSH depending on the doses administered and the routes of administration.
  • the cellular receptors for ⁇ -MSH and its counterparts are of the G type and the intra-cellular transduction takes place according to the cycle of cyclic AMP.
  • the activation of these cellular receptors is substantially inversely proportional to the doses of peptide hormones accepted by the structures of the membrane receptor.
  • the present invention is based on the search for peptide structures specifically oriented towards anti-allergic and anti-inflammatory activities on the one hand, and activators of melanogenesis on the other hand to the exclusion of any other pharmacological effect in particular at the level of the system central nervous system, like the peripheral nervous system.
  • the present invention relates to a compound comprising a peptide sequence comprising at least one sequence of
  • amino acids originating from ⁇ -MSH, the amino acids being in natural form or not, said sequence being conjugated with thioctic acid or a derivative of this acid, in the form of the corresponding salts, esters or amides.
  • amino acids can be in D, L or D, L form and the non-natural forms of amino acids correspond to derivatives, in particular substituted.
  • Thioctic acid or ⁇ -lipoic acid can be in the oxidized form:
  • One of the main objects of the present invention is the therapeutic application by the topical (cutaneous) route of the above derivatives.
  • These compounds are molecules capable of crossing the skin barrier, and of presenting the peptide fraction to cellular receptors, by inducing a biological response of the dose / effect relationship type.
  • These low molecular weight peptides whose amino acid sequences have been modified, are linked in the form of salts, esters or amides to active biochemical groups, playing a crucial role in the tricarboxylic cycle (at the level Mitochondria in particular).
  • These cofactors are lipoic or thioctic acids in oxidized or reduced form and their Lipoyl-Lysine derivatives, which are naturally covalently linked to the polypeptide chains of the cellular enzymatic system.
  • the present invention relates to peptides of 4 to 6 amino acids linked in the form of Lipoyl-Peptides and Lipoyl-Lysyl-Peptides with anti-allergic, anti-inflammatory activity and activator of melanogenesis.
  • the compounds according to the invention preferably have the peptide sequence comprising at least the following sequence:
  • amino acids possibly being in D, L or D, L form, and in particular they may be compounds having the formula:
  • Iip is thioctic acid or one of its derivatives
  • X is Glu, OH or NH2
  • Y is Trp - Gly - OH
  • Trp - Gly - NH2 Trp - NH2 Trp - OH Phe is homo Phe or p-fluoro Phe, the amino acids being in D, L or D, L form
  • the invention relates very particularly to the following compounds:
  • the position of thioctic acid corresponds to the ester or amide derivative, the acid fraction of thioctic acid providing the bond.
  • amino acid sequences mentioned above can be natural amino acid sequences or non-natural amino acid sequences. Similarly, in some cases it is possible that some of these amino acids have functions, for example they are glycosylated and / or sulfated.
  • the present invention also relates to pharmaceutical or dermo-cosmetic compositions comprising a compound as defined above.
  • compositions can be in form which can be administered orally or parenterally, intraperitoneally or injectable in particular, but preferably in form which can be administered by external topical route.
  • compositions can be, in particular, in the form of a cream, spray or lotion for example and include known excipients and possibly other active ingredients.
  • the compounds according to the present invention are useful in particular in the prevention and treatment of allergies and inflammations.
  • Peptide III whose sequence has in position 3 the amino acid paraFluoro Phenyl, is particularly oriented towards an anti-allergic and anti-inflammatory activity, by immunosuppression of Monokines (IL1, IL6, ⁇ TNF).
  • the dermo-cosmetic compositions are preferably in the form of a solution, lotion, emulsion or cream which can be used in particular as an accelerator for tanning the skin without exposure to ultraviolet rays.
  • Peptides II and TV whose sequences have in position 3 and 2 the amino acid D.homo Phényl are particularly oriented towards a stimulation of the processes of melanogenesis and activation of Tyrosinase.
  • the peptide sequences according to the present invention can be obtained by any of the methods known to those skilled in the art, in particular by methods of chemical synthesis in which thioctic acid can be integrated. In any event, given the small size of the Peptides, chemical synthesis is entirely possible and allows very pure products to be obtained.
  • Example 1 Given the small size of the Peptides, chemical synthesis is entirely possible and allows very pure products to be obtained.
  • the synthesis is carried out by the Merrifield method in solid phase using an MBHA resin and as a protective group FMOC (fluorenyl methoxy carbonyl).
  • amino acid derivatives used are:
  • FMOC Glu chex) OH which is coupled using BOP as a coupling agent.
  • BOP BOP
  • Each amino acid is used in excess (x2) as well as the BOP (x2) and each coupling is repeated 2 times.
  • Trp not dosed - Chemical mass - 887.18
  • Compound 4 (P-IV) is dissolved in physiological saline. It is quantitatively measured by spectrophotometry at 280 nm (assay of Tryptophan) which allows precise dosing of "P-IV" in the solutions which are stored at -25 ° C.
  • LPS lipopolysaccharides
  • Extracts of Escherichia Coli serotype 0127 - B8 - "Ref. SIGMA - L3137" are used at a concentration of 6 mg / ml in physiological saline. Animals:
  • mice are punctured by the retroorbital sinuses on dry tubes. As soon as the blood coagulates the clot is detached. The blood is centrifuged for 10 minutes at 1800 g at a temperature of 10 ° C.
  • the method used for this assay is of the sandwich type.
  • the samples are then deposited, and a second biotinylated anti IL1 ⁇ antibody is made to act.
  • TMB tetramethylbenzidine
  • This anti-inflammatory activity was supplemented by a study of the immunosuppressive activity of PIV with respect to Tumor Necrosis Factor ⁇ .
  • the animals in the control lots receive an injection of 0.2 ml of physiological saline by the intravenous route.
  • the animals in the PIV lots receive an injection of the product at the various doses intravenously. (Tail vein) c) Induction of TNF ⁇
  • mice Ninety minutes later all the mice are punctured by the retroorbital sinuses on dry tubes. As soon as the blood coagulates the clot is detached. The blood is centrifuged for 10 minutes at 10 ° C. at 1800 g. Once collected, the sera are frozen at - 25 ° C.
  • TNF ⁇ contained in these sera is dosed 24 hours after collection with the murine TNF ⁇ ELISA assay kit (ref. 1509-00 GENZYME) - Quick description of the Kit: the method used for this assay is of the sandwich type.
  • a first monoclonal antibody against murine TNF ⁇ is used.
  • the samples are then deposited and a second anti TNF ⁇ goat antibody is made to act.
  • the revelation takes place with a donkey antibody to goat immunoglobulin, labeled with peroxidase.
  • the colored reaction uses o-phenylene diamine (OPD).
  • OPD o-phenylene diamine
  • mice C57 BL / 6JICO female mice, 5 weeks old, are divided into ten batches of ten animals (five per cage), with free access to water and food, subjected to a photoperiod of twelve hours of light per twenty- four hours.
  • the animals of lots I to 6 receive daily and by topical application on the shaved skin of the back, the products to be studied, dissolved in propylene glycol, in a constant volume of 50 ⁇ l and this for five consecutive days.
  • mice On the fifth day, thirty minutes after the last application, all the mice are sensitized with 25 ⁇ l of DNFB (2.4 - Dinitro - 1
  • FluoroBenzene (FLUKA CHEMIKA PURUM 97% lot no. 33820890) 2% in a 4 for 1 mixture of acetone (SDS ref 0510) and triolein (FLUKA) applied topically to the dorsal region of shaved skin.
  • a new sensitization is carried out by applying DNFB.
  • the thickness of the ears of the mice is measured using a micrometer (ROCH 0 to 25 mm at 1/100 mm) in order to obtain basic values, then the ears are stimulated by application topical of 20 ⁇ l of DNFB at 0.8 96.
  • the average value of the thickening of the ears is established for the mice of the batches which have received the products to be studied, as well as for the mice of the control batch. The percentage of possible deletion will be expressed by the
  • mice day 1 2.5 ng / mice day
  • the fibroplasts are cultured in microwells (24-well plate of 2 cm 2, Falcon).
  • the innoculum is 30,000 cells per well; the nutrient medium used is composed of RPMI 1640 (90%) and decomplemented fetal calf serum (SVF, 10%).
  • the medium is changed every two days until the cells meet.
  • the single-cell layers thus obtained are washed and then preincubated for 24 hours in fresh medium containing only 1% of FCS.
  • the substances to be tested are added to the medium at different concentrations between 10-6 and 10-4 M. After 20 minutes of incubation in the presence of these compounds, the recombinant human IL1 (Tebu, France) at the concentration of 5, 2.5 or 0.5 ng / ml of medium is brought into contact with cells for 18 hours.
  • the RIA assay is carried out according to the method described by Dray et al. (Europ. J. Invest. 1975). 3 series of duplicate experiments were carried out for each concentration of product studied and for the controls. The results are expressed in pg / ⁇ g of DNA. The inhibitory effect is expressed as a percentage relative to the controls.
  • the DNA was assayed by fluorimetric method according to the protocol described by Brunk et al. (Analytical Biochem., 1979).
  • IL1 5 ng 7576 ⁇ 310
  • PIII and PIV have an inhibitory effect on the action of IL1 and PGE2.
  • the skin fragments are then subjected to an enzymatic hydrolysis by protease K for 72 hours at 45 ° C.
  • the melanin assay is carried out at 405 nm using a Multiskan - Titertek - MCC - 340, compared to a standard melanin range Sigma M. 8631
  • % stimulation _2__L_Q_ ⁇ 100
  • the dermal cream containing PVI administered topically highly induces the synthesis of Melanin in the epidermis (+ 71%).
  • This activity in accordance with the object of the present invention is linked to the chemical structure of PVI which contains N.Lipoyl - Lysine and D.homoPhenyl groups.
  • the dermal cream whose formula contains PIII administered topically, has no activity on the stimulation of Melanogenesis
  • Solvent propylene glycol previously used as a control in Example 10.
  • a measurement of the activity of the witness will be carried out for each experiment.
  • mice On the fifth day, thirty minutes after the last application, all the mice are sensitized with 25 ⁇ l of D.N.F.B. (2.4-Dinitro-l
  • FluoroBenzene (FLUKA CHEMIKA PURUM 97% lot no. 33820890) 2% in a 4 for 1 mixture of acetone (SDS ref. 05510) and triolein (FLUKA) applied topically to the dorsal region of shaved skin.
  • the thickness of the ears of the mice is measured using a micrometer (ROCH 0 to 25 mm at 1/100 mm) in order to obtain basic values, then the ears are stimulated by application 20 ⁇ l topical DNFB at 0.8%.
  • the average value of the thickening of the ears is established for the mice of the lots which have received the products to be studied, as well as for the mice of the control lot.
  • the percentage of possible deletion will be expressed by the calculation
  • Lot 1 Lot I: Lot I: 100 ng / mouse / day 10 ng / mice / day 1 ng / mouse / day
  • Lot II Lot II: Lot II: 1 ng / ⁇ ouri ⁇ / day 10 ng / mouse / day 100 ng / mouse / day
  • Sample to be analyzed - compound 4 PIV Biological material Embryonic cells isolated in in vitro culture in a defined, purely saline medium (standard culture conditions: 2 ml of medium / culture).
  • the embryonic territory is removed (from the Pleurodele embryo and from the Axolotl embryo) from the first stage of melanogenesis, immediately after melanocyte induction.
  • the neural bead which has just individualized, contains all of the melanoblastic precursors.
  • the cultivation of the cells of the neural bead and the underlying mesoderm makes it possible to cocultivate (under totally identical) melanoblasts with different other cell precursors belonging to various categories: myoblast neuroblasts, epidermal cells, fibroplasts, mesenchymal cells.
  • the 2 doses are therefore used for this work: 0.1 and 1 ⁇ g / ml.
  • the stimulation of melanogenesis relates to the size of the melanocytes which increases by a factor x 4 and even x 5 after 8 days of culture for treatment with 1 ⁇ g / ml.
  • the stimulating effect of PIV also relates to the quantity of biosynthesized melanin.
  • the treated melanocytes show no apparent sign of cytotoxicity. In addition, they have a lifespan equivalent to that of control melanocytes in vitro.
  • Neuroblasts embryonic origin of the SNP
  • the neuritic network in the treated cultures consists of shorter and more dispersed neurites than the control neurites. This observation should be analyzed in more detail. All the observations and quantifications were carried out on several experimental series in order to perfectly control the reproducibility of the phenomena described.
  • PI and PIV treatment of melanocyte precursor embryonic cells stimulates their differentiation both on a qualitative and a quantitative level.
  • the number of melanocytes increases at least by a factor of 2 per culture.
  • the quantity of biosynthesized melanin per cell also increases by an equivalent factor (1.4 ng / cell) after eight days of culture.
  • PI and PrV stimulate the differentiation of melanoblasts. It is important to emphasize the following remarkable result: they do not stimulate the precursor embryonic cells not yet determined in the melanoblastic pathway. They are therefore not inducers and only target the melanoblast: no effect on the precursor cells; stimulating effect on already induced melanoblasts). Analysis of the cytotoxicity of PI and PIV
  • the two peptide formulas studied have no effect, toxic or stimulating, on neuroblasts or neurons.
  • the size of the cell bodies, the length and the number of neurites, the ultrastructure and finally the lifespan of the neurons treated are equivalent to those of the control neurons.
  • astrocytes No toxic effect is observed on astroglial cells treated with PI and PIV which differentiate normally and without delay compared to control astrocytes.
  • Myoblasts spread and differentiate without delay and without anomaly compared to myoblasts -control. - Fibroblasts, mesenchyme
  • - PI and PIV have no stimulating effect on the other cell types studied: neurons, astrocytes, muscle cells, fibroplasts, ...

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Toxicology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Cosmetics (AREA)
EP94928428A 1993-09-22 1994-09-22 Peptidderivate von alpha-msh und deren anwendung Expired - Lifetime EP0669938B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9311281A FR2710340B1 (fr) 1993-09-22 1993-09-22 Dérivés peptidiques de l'alpha-MSH et leur application .
FR9311281 1993-09-22
PCT/FR1994/001108 WO1995008564A1 (fr) 1993-09-22 1994-09-22 DERIVES PEPTIDIQUES DE L'α-MSH ET LEUR APPLICATION

Publications (2)

Publication Number Publication Date
EP0669938A1 true EP0669938A1 (de) 1995-09-06
EP0669938B1 EP0669938B1 (de) 1999-04-14

Family

ID=9451116

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94928428A Expired - Lifetime EP0669938B1 (de) 1993-09-22 1994-09-22 Peptidderivate von alpha-msh und deren anwendung

Country Status (9)

Country Link
US (1) US5830994A (de)
EP (1) EP0669938B1 (de)
JP (1) JPH08503963A (de)
AT (1) ATE178904T1 (de)
AU (1) AU7785994A (de)
CA (1) CA2149925C (de)
DE (1) DE69417868T2 (de)
FR (1) FR2710340B1 (de)
WO (1) WO1995008564A1 (de)

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WO2005009402A3 (fr) * 2003-07-18 2005-08-04 Inst Europeen Biolog Cellulair Association d’un agent peptidique et d’un filtre uvb dans le traitement de l’alopecie

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WO2005009402A3 (fr) * 2003-07-18 2005-08-04 Inst Europeen Biolog Cellulair Association d’un agent peptidique et d’un filtre uvb dans le traitement de l’alopecie

Also Published As

Publication number Publication date
CA2149925C (fr) 2009-09-15
JPH08503963A (ja) 1996-04-30
DE69417868T2 (de) 2000-05-31
AU7785994A (en) 1995-04-10
US5830994A (en) 1998-11-03
FR2710340B1 (fr) 1995-12-15
FR2710340A1 (fr) 1995-03-31
CA2149925A1 (fr) 1995-03-30
WO1995008564A1 (fr) 1995-03-30
DE69417868D1 (de) 1999-05-20
ATE178904T1 (de) 1999-04-15
EP0669938B1 (de) 1999-04-14

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